Prostate cancer (PCa) is the second leading cause of cancer deaths in US men. The TMPRSS2/ERG (T/E) fusion gene occurs in 50% of PCas and has multiple biological activities that can promote tumor progression. We have shown using gene knockdown targeting the T/E fusion gene can markedly decrease tumor growth in vivo. Thus the T/E fusion gene is an outstanding therapeutic target in PCa. The T/E mRNA fusion junctions are present only in PCa cells since these two genes are not transcribed into a single mRNA in normal cells. Specifically targeting these junctions using highly specific siRNAs should not have any specific off-target effects in normal tissues so toxicity should be minimal. We have recently developed non-toxic liposomal nanovectors. We have used these nanoliposomal vectors to deliver gene knockdown agents (siRNAs) targeting the fusion junctions in vivo and seen significant anti-tumor effects without toxicity. However, we need to further enhance delivery in order to maximize therapeutic efficacy since the ERG protein was not completely eliminated and tumors continue to grow, although at slower rates. We will try several approaches to increasing siRNA delivery. First, several chemical modifications of the nanoliposome will be used to both increase stability in the circulation and target tumor cells. Second, we will use drugs that are already in common use to enhance intratumoral nanoliposome delivery. Docetaxel chemotherapy is widely used to treat advanced PCa but is not curative. Radiation therapy is also a major therapy for PCa. Our preliminary data indicates that knockdown of the T/E fusion can enhance these therapies in vitro. We will determine if the optimized knockdown of the T/E fusion gene in vivo using non-toxic siRNA approaches can be used to enhance the efficacy of these therapies in PCa. A significant advantage of such targeted adjuvant therapy is that it will be tumor specific and thus minimize side effects in non-tumor tissues. The ultimate goal is to translate these approaches into clinical practice that will positively impact survival for men with PCa. As a monotherapy nanoliposomal SiRNA knockdown may be useful in men with advanced PCa. Every year tens of thousands of men receive docetaxel or radiation therapy for PCa and fail such therapies and thus there is a pressing clinical need to enhance these therapies. Significantly, the lack of toxicity of DOPC nanoliposomes has already been established in primates. Thus there is a clear path forward to translate our preclinical studies into clinical practice to benefit men with prostae cancer.